1. Field of the Invention
The present invention relates to a novel device which is useful for releasing drug into aqueous environments of the body. More particularly, the invention relates to a new sustained release delivery device for drugs which enables the release of drugs at a substantially constant rate over a prolonged period of time.
2. Description of the Prior Art
Many sustained release formulations of drug and polymer are described in the medical art literature. Most of these formulations release their drug by either (1) diffusion, in which the drug diffuses through the polymer or the polymer swells with body fluid and the drug is leached from the polymer by such fluid, or (2) erosion, in which the polymer disintegrates or dissolves in body fluids to release entrapped drug. The release of drug from the present invention is not governed by such diffusion or such erosion.
Controlled release drug delivery systems that operate as osmotically driven pumps are also known. For instance, U.S. Pat. No. 3,916,898 describes a system that consists of an osmotically effective drug core encapsulated by a drug impermeable, water permeable coating. The coating has one or more specifically sized outlets in it. The core may consist of a mixture of a drug, such as pilocarpine nitrate, and a polymer binder, such as ethylene-vinyl acetate copolymer. Initially water permeates through the coating to dissolve part of the drug core. Additional water is then imbibed by the core to generate hydrostatic pressure within the core that causes the drug solution to be pumped out through the outlet port(s) in the coating. In contrast the devices of the present invention do not include a coating with defined outlet ports. Instead the present devices consist of a mixture of drug of specific particle size and polymer in specific volume proportions. The parameters governing the release rate of drug from these devices are different than those governing the release rate from the osmotically driven pumps.
U.S. Pat. No. 3,427,066 describes medicinal beads that release drug by a bursting mechanism. The beads consist of a core of water-swellable colloid containing a drug and a thin coating of polymer that is inert to gastrointestinal fluids and permeable to water. When the beads are ingested, water diffuses inwardly through the polymer coating causing the colloid core to swell. This swelling creates sufficient pressure to burst the polymer coating, thereby releasing the entire quantity of drug in the core. The present invention releases drug by a bursting mechanism but not one that involves beads that have a water-swellable colloid core.
U.S. Pat. No. 2,478,182 describes salt tablets in the form of a tablet of compressed salt granules coated with cellulose nitrate of acetate. According to the patent the cellulose derivative penetrates the tablet and forms a honeycomb structure around the compressed granules. Upon ingestion water dialyzes into the compartments of the honeycomb and salt dialyzes out. When the compartments become engorged with water, the compartments burst and liberate salt. The tablets are exhausted in 60-80 minutes. In comparison the devices of the invention provide truly sustained release at a substantially constant rate. The proportion of polymer in the invention devices is grossly larger than that of the salt tablets. Also, the particle size of the sale granules is not in accord with the drug particle specifications of the invention.
The agricultural chemical art literature describes various slow release formulations of fertilizer or pesticide and polymer. Numerous agricultural chemical art references are cited in the files of the above-mentioned cross-reference parent U.S. patent applications. Those references are generally concerned with achieving only slow release of a chemical and are not concerned with the controlled, precise release associated with the present invention. None of these references suggest that chemical is released by a bursting mechanism and the few that mention a release mechanism at all indicate that release occurs via diffusion or erosion similar to that described above.
"Anti-Fouling Paints", Masson, F., J. Applied Chem., Vol. 19, pages 93-99, April 1969, an article totally unrelated to the medical art, describes a mechanism similar to the bursting mechanism by which the present invention releases drug. This article relates to "contact-leaching" marine paints, that is, paints that contain enough pigment for direct contact to occur between adjacent pigment particles in the paint vehicle, such that as one pigment particle is dissolved by the leachate, the adjacent one is exposed to the leachate. It is specifically concerned with explaining the deviation between the actual leaching kinetics and the theoretical leaching kinetics of such paints. A mathematical paint model is proposed consisting of a single, soluble pigment in a stable, insoluble resin vehicle, with the individual pigment particles wet completely by the vehicle. In a layer of such paint, the pigment particles are postulated to be encased in a thin film of resin that exhibits brittle fracture under stress. It is postulated that (a) as one particle is leached from the layer, the thin film of resin that separates it from the adjoining particle is exposed to the leachate, (b) the leachate diffuses through the resin film and dissolves some of the adjoining pigment particle, (c) the resulting osmotic pressure ruptures the film, and (d) the solvated pigment diffuses out through the thus formed interconnecting holes in the layer. This article is believed to be irrelevant to the present invention because it is in an unrelated art and is not concerned with dispensing materials but rather with explaining the leaching kinetics of marine paints.